Design Space and Regulatory

Flexibility – A Way Forward

EFPIA Team producing
Mock P2 Document
Chris Potter AZ (Chairman)
Rafael Beerbohm Boehringer-Ingelheim
Alastair Coupe Pfizer
Fritz Erni Novartis
Gerd Fischer Sanofi-Aventis
Staffan Folestad AZ
Gordon Muirhead GSK
Stephan Roenninger Roche
Alistair Swanson Pfizer
 Use of Design Space
(A simple example)
Supports
• Continuous improvement
• Change without prior approval
– Scale, site, packaging
• Making process validation redundant
• Moving to Real Time Quality Control
(reduce/remove end product testing)
• Reduction of confirmatory stability studies

2
 Concepts Included

• Use of models and algorithms

• Use of in-line and at-line tools
• Design Space based on prediction
• Design Space not requiring ‘edge of failure’
• Link of Control Strategy to Design Space (Q8)
• Use of Q9 principles of Quality Risk
Management

Not all information may be available at time of

initial filing.
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Pharmaceutical Development Approach
Target Product Profile

Drug substance properties; prior knowledge

Proposed formulation and manufacturing process

(Risk Identification)

Cause and effect process

(Risk Analysis)

Risk-based classification
(Risk Evaluation)

Proposed Parameters to investigate (e.g. by DOE)

(Risk Reduction)

FORMULATION PROCESS DESIGN

DESIGN SPACE CONTROL STRATEGY SPACE BY UNIT
(Risk Reduction)
OPERATION
4
 Pharmaceutical Development
The example
• Immediate release tablet
• 20mg active, highly soluble, highly permeable
drug (BCS Class I)
• Drug properties
– Low bulk density, crystalline, single stable
polymorph
– Primary amine salt
– Some susceptibility to aqueous degradation

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 Target Product Profile

Description Round normal convex uncoated tablet

Identification Positive
Assay 20 mg ± 5% active at time of manufacture
Degradation products Qualified meeting ICH Q3B and Q6A criteria
Dissolution Immediate release
Uniformity of dosage units Meets pharmacopoeial acceptance criteria

Microbiological limits Meets pharmacopoeial acceptance criteria

6
 Proposed Formulation and
Manufacturing Process
Key Formulation Design Decisions

DirectU
Compression High bulk density

Wet Granulation

U
Lactose Primary amine
Mannitol

7
Proposed Manufacturing Process
Fluidized Bed
Dryer
Dispensing Granulation

Scale
Air

Blending

Tableting

Unit Operations

Packaging

8
 Cause and Effect Process

Drying Analytical

Temp

RH

Air Flow Sampling

Shock Cycle Method

Water
Drug
Content
Operator Precompressing Water Substance
Temp/RH Main Compressing Binder Age
P.S.
Operator Feeder Speed Temp Process Conditions
LOD
Training Press Speed Spray Rate
Diluents
Punch Penetration
Depth Spray Pattern

Tooling P.S.
Plant Feed P.S.
Scrape Down
Factors Frame LOD
Chopper Speed Other
Compressing
Mixer Speed Lubricant
Disintegrant
Endpoint Raw
Binder
Materials
Power
Granulation
Time

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 Initial Classification of Importance of Unit
Operation to Have an Impact on Quality
• Write down, what you know already
Unit operation
Quality Attributes
 Example of Formulation
Development DOE (3.2.P.2.2.1)
Previous knowledge

Potential Formulation

DOE

Independent Variables Dependent Variables

Levels of excipients Disintegration
Dissolution
Hardness
Appearance
Degradation rate
Dose uniformity
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 Magnesium Stearate
Design Space 1-3%
Compression Force (kN) vs Crushing Strength (Kp)
Effect of Lubricant Level

16.00

14.00

12.00
Crushing Strength (Kp)

10.00

8.00

6.00

4.00

2.00

0.00
0 5 10 15 20 25 30 35
Compression Force (kN)

12
 Dissolution Profiles made with
Different Lubricant Levels
120

100
Mean % dissolution

80
1% Mg St
60 2% Mg St
3% Mg St
40

20

0
0 5 10 15 20 25 30 45
Tim e (m inutes)

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 Magnesium Stearate
Design Space
• One dimension – univariate range
• No edge of failure
• Maybe not useful in this case as a formulation
variable
• Does help conclude a robust formulation
• Risk of failure of dissolution, disintegration,
hardness at blending step significantly
reduced

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 Key Process Variables for Wet
Granulation
Wet granulation parameters Input material attributes
Mixing speed API particle size
Water addition rate Mannitol particle size
Mixing time

Dependent variables for tablets

Appearance
Assay
Degradation
Dissolution/Disintegration
Uniformity of Dosage Units

+ Suitability parameters for next processing step 15

 Relative Importance of Process Parameters on
Disintegration from Coefficient Plot from Partial
Least Squares (PLS) Model

DoE Coefficients for Disintegration

3

Series1

0
Drug Substance Mannitol PS Mixing Speed Water Amount Wet Mixing Time Compression Force

-1

-2

-3

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 Effect of Water Addition Rate and Mixer Speed on
Disintegration (red does not meet quality requirements)

Disintegration

Water addition rate

Faster

Mixer speed

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 Examplain: Drying Operation
Inlet Temp Bed Temp
Outlet RH
Air flow
Outlet Temp
Fluid Bed Drier

Wet granule Dry granule

Water content Water content

NIR FBRM
API Size distribution Particle size
water content granule size
distribution
controlled by
granulation operation

colour code: Red - input variables; Green - derived parameters; Blue - on-line measurements

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Process Variables and Quality Attributes for the
Fluid Bed Drying Operation
Process variables
Drying parameters Input material attributes
Inlet air temperature Water content
Inlet air humidity Granule particle size distribution
Air flow rate
Fill level
Filter sock cycle
Heating rate
Cooling rate
Quality attributes
Dried granule Tablet
Particle size distribution (fines) Disintegration
Water content Dissolution
Degradation (des-ethyl Weight uniformity
examplain)
Content uniformity
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Effect of inlet temperature and air flow on degradation and
generation of fines, as shown by the DOE (red = does not
meet quality requirements) (1 kg scale)
Degradation Fines
Inlet temperature

Inlet temperature

Air flow Air flow

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Interaction of Inlet Temperature and Air
Flow for Combination of Failure Modes
(Red = Does Not Meet Quality
Requirements)

Degradation and fines

Inlet temperature

Air flow
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 Examplain Design Space –
Graphical Description
(1 kg Scale)
18.5%
17.5% Regions of uncertainty
Known edge of failure due to fines
%
Known edge of failure due to degradation
H2O

Trajectories describing the

boundaries of the design space
where product quality is assured
2.0%
1.5%

Drying time
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 Process Trajectories for 5 Batches
Manufactured at 25 Kg Scale

18.5%
17.5%
ICH registration stability batches
Test batches (see text)
%
H2O

Trajectories describing the

boundaries of the design space
where product quality is assured
2.0%
1.5%

Drying time

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 Summary: Design Space for Fluid
Bed Drying
• Multivariate for degradation, disintegration,
uniformity of content
– Inlet temperature
– Air flow
– Drying time
• Trajectory for water content, a critical
parameter
• Change of scale understood
• Areas of failure found in this case
• Clear control strategy
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Use of Design Space for Fluid Bed Drying
Manufacturing changes
– Change of fluidised bed dryer
– Allows change of packaging within pre-defined criteria

Introduce real time release, linked to risk

management tools and based on
Process Understanding
– Quality parameter output assured
– Process controlled and monitored (advanced process
control strategy)
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Use of Design Space for Fluid Bed Drying

Process validation is redundant

– Process reproducibly produces material
for blending and compression
Change of site and scale
– Scale factored into design space
– Site independent

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 Determination of Design Space –
Conclusions
• Requires experimentation or prior knowledge
– But not necessarily formalised designs such as
factorials
• Can be a very simple or more complex concept
– May require multi-factorial approaches using PAT
tools
– Could (will) be multidimensional
• Per definition, quality attributes of the finished
product are achieved when operating within the
Design Space
• As a consequence, any process modification within
design space should be acceptable without any
further regulatory approval
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